The Gastrointestinal Cancers (GIC) Program is fully integrated, involving the collaboration of basic, translational, and clinical investigators. The overall Program goal is to prevent and treat Gl malignancies by 1) defining the genetic and molecular determinants that promote their pathogenesis and 2) utilizing these findings to develop preventive, early diagnostic, and precise therapeutic strategies. Major accomplishments in the last funding cycle include 1) definition of the clinical features of non-syndromic familial high-risk colon cancer, 2) identification of a American founder mutation of attenuated FAP that could account for up to 1% of colon cancer cases in this country, and, 3) definition of novel molecular signaling pathways responsible for initiation and progression of colon tumors following loss of APC. These findings have led to new hypotheses currently under investigation in two therapeutic and two preventive clinical trials. Led by Randall Burt, MD, and David Jones, PhD, the GIC Program includes 19 members from seven departments and two colleges. As of December 2008, members had $3.5M in peer-reviewed annual direct costs for research projects, of which 86% was from NCI. Since July 2003, our research efforts have resulted in 213 publications, of which 16% were intra- and 42% were inter-programmatic collaborations. Eight new members have joined the GIC Program, including four clinical (MD) and four basic science (PhD) researchers. During 2008, the GIC Program had 13 investigator-initiated trials and 12 other clinical trials; 39 subjects were recruited to therapeutic trials and 176 subjects recruited to other trials. The GIC Program adds value to HCI with numerous collaborations, including a colon cancer-focused Program project and a number of joint grants with investigators of other Programs. Our broad expertise allows a fully integrated approach to Gl cancers, partnering basic, translational, and clinical investigators in common research efforts. The strength of the Program also helps in recruiting new faculty. The Program has been essential in developing key infrastructures, including a familial colon cancer clinic and registry; a clinical research center with endoscopic capabilities; a population database for access to familial cases; and a regional Gl network for access to and care of patients. Plans include continuation of the Gl cancer focus group with added emphasis on bringing laboratory findings to the clinic, expanding and coordinating pancreatic cancer efforts, building on identified susceptibility loci in Gl cancers to effect gene discovery, clarification of APC and Wnt pathway discoveries to lead to clinical applications in both syndromic and nonsyndromic settings, and expanding research in lipid mediator and inflammatory pathways as they apply to cancer pathogenesis. Recent recruit Dr. Sunil Sharma, a senior Gl oncologist, will play a major role in the Gl clinical trials program; one additional clinical oncology investigator will be added. Together, they will greatly increase our ability to implement basic science discoveries in clinical trials of prevention and treatment.